Leponeks

Leponex is an antipsychotic that is significantly different from standard neuroleptics and is used in the treatment of schizophrenia, which is not amenable to therapy, carried out with the introduction of these medicines.

Performed testing of the drug did not reveal his ability to provoke catalepsy, and in addition to the suppression of stereotypical behavior, which is noted in the case of use in the treatment of amphetamine or apomorphine.

[1], [2]

Indications Leponeks

It is used in the case of schizophrenia, in situations where the use of conventional neuroleptics does not bring results or the patient has a strong sensitivity to these drugs.

The lack of effect from the use of conventional neuroleptic is diagnosed if the patient does not show positive dynamics when the drug is administered in accordance with the selected dosage regimen and the use of 2+ medicines from the above category.

Hypersensitivity with respect to standard neuroleptics is determined in the absence of any positive dynamics, as well as the appearance of intense side effects that have a neurological etiology.

[3]

Release form

The release of the medical product is sold in tablets, 10 pieces inside the cell packs. In a box of 5, 10 or 12 or 25 packs.

[4], [5]

Pharmacodynamics

The drug slightly slows down the activity of dopamine D1, D2, as well as D3 and D5-terminations, but it is extremely intensively blocking the action of dopamine D4-terminations. The drug has potent antihistamine, α-adrenolytic, and anticholinergic properties, and has antiserotonergic activity.

When performing clinical tests, the ability of drugs to a pronounced and rapid sedative effect was determined, and in addition to a strong antipsychotic effect, observed in people with schizophrenia and resistance to treatment with other antipsychotics.

The effect of the drug and the relatively productive manifestations of schizophrenia, cognitive disorders and signs of prolapse are observed. A direct link was found between the positive dynamics and the duration of use of Leponex. With the introduction of this tool, the number of suicide attempts decreases Vsemora compared with persons who use standard antipsychotics.

There is an extremely low number of side effects that appear (extrapyramidal disorders, parkinson-like symptoms and akathisia), and at the same time there is a weak effect on prolactin levels (this minimizes the likelihood of amenorrhea, impotence, gynecomastia or galactorrhea) compared to the usual neuroleptic.

But at the same time, the use of Leponex can provoke intensive granulocytopenia or agranulocytosis, developing, respectively, in 3%, as well as 0.7% of all cases. Given the severity of these diseases, medication can be prescribed only when resistance is diagnosed or hypersensitive to conventional antipsychotics.

[6]

Pharmacokinetics

Leponex has an intense absorption - 90-95% when taken orally, without reference to the use of food.

Clozapine, which is the active element of the drug, is almost fully exchanged after the 1st intrahepatic passage. Of the developed metabolic components, only one has a medication effect (desmethyl derivative). It acts like clozapine, but the severity and duration of its activity is much lower.

The level of bioavailability of the drug is 50-60%. To obtain indices of intraplasma Cmax it is required in the range of 0.4-4.2 hours (the average value is 2.1 hours).

Vd values are 1.6 l / kg. Intraplasmic synthesis with protein is 95%.

Removal processes are implemented in 2 stages. The term half-life of the final stage varies in the range of 6-26 hours with an average of 12 hours. After a single dose of 75 mg, the average term for the terminal half-life is 7.9 hours and increases to 14.2 hours with a 7-day use of 75 mg per day. The level of AUC depends on the size of portions of drugs.

Excretion is realized mainly in the form of metabolic elements through renal and intestinal secretion (by 50%, respectively, as well as 30%). Inside the feces with urine only traces of the active element are found.

[7], [8], [9], [10], [11], [12]

Dosing and administration

The medication can be used exclusively for medical purposes.

Because the medicine can cause the appearance of agranulocytosis, the doctor prescribes it to people with schizophrenia under the following conditions:

• people who use conventional antipsychotics do not lead to a positive result, or there is a hypersensitivity to such drugs;
• Persons who have previously tested the “white blood” values, and its result is within the normal range (leukocyte formula and white blood cell count);
• people who do not have problems with regular monitoring of the number of neutrophils with leukocytes inside the blood (1 time per week during the first 4 months of the course, and then 1 time per month, and another 1 month after discontinuing Leponex).

The medical specialist should be very careful in prescribing the medicine, first examining the patient’s history and data of blood tests, and also finding out which patient the drug uses systematically.

The patient should be informed of the need to regularly visit the doctor for consultations, and follow all his recommendations. It is imperative to inform the physician about any changes in health, especially if symptoms of infection or flu-like manifestations appear (pain in the throat, hyperthermia, etc.), because they may be precursors of neutropenia.

Dosing regimen is selected individually, starting with the introduction of low doses of drugs (12.5 mg 1 time per day), and then determining the minimum effective dosage.

When systematically receiving agents that lead to clinically significant interactions with clozapine (SSRIs or benzodiazepines, etc.), it is required to select a regimen that takes these data into account, and also, if necessary, change the recommended portion accordingly.

Dosage regimens of the drug.

Initial portions.

On the first day, 12.5 mg is administered, 1-2 times a day; in the second - 25-50 mg, 1-2 times. Later, if no negative symptoms are noted, the daily dosage is gradually increased by 25-50 mg in order to get a portion of 0.3 g after 2-3 weeks.

If the doctor decides that a subsequent increase in servings is required, it should be done less intensively - by 0.05-0.1 g, 2 times a week (but it is recommended 1-fold in 7 days).

Medical dosing.

The required antipsychotic effect is observed in most people with schizophrenia with the introduction of 0.3-0.45 g per day (the portion is divided into several uses (uneven parts are possible), prescribing the highest amount of drugs in the evening). Taking into account the personal characteristics of the patient, as well as the course of the disease, the minimum effective portion can vary in the range of 0.2-0.6 g per day.

The intensity and effectiveness of the developing medical influence is personally assessed by the treating doctor.

Maximum portion sizes.

A personal response to the treatment being performed may require a subsequent increase in daily dosage (above 0.6 g), but it cannot be more than 0.9 g.

It is necessary to take into account that the intensity of negative signs is directly proportional to the increase in dosage of drugs. Extremely careful monitoring of the patient’s condition is necessary immediately after exceeding the daily portion of 0.45 g, which may increase the severity of negative symptoms (seizures, etc.).

Supporting portions.

After reaching the maximum drug activity, often go to support portions. Reduce the dosage also need to gradually. The maintenance course should last at least 6 months. After establishing such a portion of less than 0.2 g per day, you can take Leponex 1-fold, in the evenings.

Cancel medication.

With the planned abolition of drugs by a doctor, it is necessary to gradually reduce portions to the minimum mark (over a period of 7-14 days to reduce the likelihood of withdrawal).

When there is an urgent need to cancel the medication (if leukopenia is detected), it is necessary to strengthen the patient's medical observation, because there is a likelihood of exacerbation of psychotic symptoms and development of withdrawal symptoms (with nausea, loose stools, vomiting and severe headaches). Influence of drugs.

The introduction of the drug after the interval.

If the drug was missed for more than 2 days, it is resumed with a dose of 12.5 mg, 1-2 times a day. On the 2nd day, if there is no hypersensitivity, it is possible to increase the dosage more intensively (before getting the therapeutic one) than with the initial therapy.

If during the first treatment cycle the patient has severe disorders of the respiratory and cardiac function, with repeated use of the drug, the dosage is increased even more slowly and with extreme caution.

The dosage regimen of medication in cases where it is transferred from neuroleptics.

Starting the use of Leponex is allowed after a minimum of 7 days from the moment you stop taking antipsychotics. With the need for urgent administration of the drug, it is necessary that at least 24 hours pass since the last use of the antipsychotic. Dosages are selected according to the schemes described above.

It is forbidden to combine the drug with other neuroleptics.

Use in the elderly.

For the indicated group of patients, the size of the initial portion per day should be a maximum of 12.5 mg, with a single dose. Later, a very slow increase in dosage to the therapeutic point - a maximum of 25 mg per day.

It is also necessary to take into account that the drug effect and safety of Leponex in the treatment of schizophrenia in the elderly have not been studied enough.

During testing, an increased degree of development of negative symptoms was observed compared with younger patients (tachycardia, orthostatic collapse, etc.). In addition, in the elderly, an increase in the frequency of development of anticholinergic drugs (postipation, involuntary urination, etc.) is possible.

[17]

Use Leponeks during pregnancy

When performing preclinical tests, the pathological influence of the drug on the fetus was not observed, as well as reproductive disorders in women. But given the small number of studies related to the safety of drugs in pregnant women, it is allowed to prescribe it during this period only with strict indications and medical evaluation of the possible consequences.

In addition, during preclinical tests, the ability of the drug to excretion with breast milk was found, therefore, it is impossible to combine breastfeeding and taking medication.

Contraindications

The main contraindications:

• severe intolerance to the components of drugs;
• established agranulocytosis or granulocytopenia, which has an idiosyncratic or toxic nature (except for the aforementioned diseases that have developed due to the use of chemotherapeutic substances);
• presence of bone marrow dysfunction;
• established epilepsy that cannot be treated;
• psychosis associated with the abuse of alcohol or other toxic agents, and in addition to this coma and drug poisoning;
• vascular collapse or a strong slowing down of the CNS action in various forms;
• the presence of intense disorders of a nephro or cardiac nature (for example, myocarditis);
• diagnosed intensive hepatopathology of different genesis, during which there is a loss of appetite, nausea and jaundice.

[13], [14]

Side effects Leponeks

Among the adverse events:

• damage to hematopoietic function: a significant increase in the likelihood of developing granulocytopenia or agranulocytosis. Most often, their appearance (about 85% of cases) occurs during the first 4 months of therapy. Due to agranulocytosis, sepsis can develop with subsequent death, therefore, before using the drug and during treatment, it is required to monitor the indicators of leukocytes together with the leukocyte formula. With the development of such a disease, the medication is immediately canceled. Eosinophilia or leukocytosis may develop (most often it is observed in the first weeks of the course). Thrombocytopenia may occur;
• CNS disorders: severe drowsiness or fatigue, dizziness, high intensity sedative effects, headaches and changes in ECG readings. Perhaps the emergence of myoclonic signs or generalized convulsions, whose severity depends on the size of the dose. The risk of occurrence of these disorders increases significantly in the event of a sharp and rapid increase in the dose of drugs and in epilepsy in a patient. After the onset of such symptoms, you should immediately reduce the dose of Leponex and prescribe (if necessary) anticonvulsants (except carbamazepine, because it suppresses the work of the bone marrow). It is also possible the emergence of increased anxiety, delirium, disorders of consciousness, muscular weakness, arousal of nervous nature, tremor, extrapyramidal disorders (they are more weakly expressed than in the case of ordinary neuroleptics) and akathisia. In the case of a combination of drugs with lithium drugs, an MNS occurs;
• problems associated with the autonomic NS: hyposecretion affecting the salivary glands, or hypersalivation, hyperhidrosis, visual disturbances and disorders associated with the thermoregulatory center;
• disorders of the CVS function: intense orthostatic collapse or tachycardia, with which loss of consciousness is possible (noted in the first weeks of treatment), an increase in blood pressure, severe vascular collapse, changes in ECG data and thromboembolism. In addition, myocarditis, pericarditis, or a heartbeat disorder that may cause death may develop. It is necessary to carefully monitor the state of the person being treated and, in case of signs of myocarditis (with subsequent diagnosis of the disease), cancel the medication;
• disorders of respiratory activity: the suppression of the respiratory center (can reach the complete cessation of the respiratory processes), which may be accompanied by a collapse of the vessels. There may be aspiration of the stomach contents (food inside the stomach or gastric juice penetrates the respiratory ducts), an increased risk of which is observed in people with dysphagia, or when taking large portions of drugs;
• lesions affecting digestion and gastrointestinal tract: nausea, constipation, intestinal blockage and vomiting. In addition, liver inflammation, a temporary increase in the activity of the action of intrahepatic enzymes, an active phase of pancreatic inflammation, intrahepatic cholestasis (the medication must be stopped) and hypertrophy affecting the parotid glands are noted;
• disorders associated with the urogenital system: urinary retention or involuntary development of this process, as well as priapism. The active phase of tubulointerstitial nephritis may be observed;
• other symptoms: weight gain, epidermal rashes, benign hyperthermia (usually in the first weeks of treatment) and intense hyperglycemia, causing the development of ketoacidosis.

The fact of unexplained deaths has been diagnosed in psychiatric patients with therapy intolerance, and in addition in connection with taking medication or other antipsychotics.

[15], [16],

Overdose

Dosage of this medicine must be extremely cautious, because in the case of poisoning in 12 cases out of 100 death occurs. The consequences of intoxication are personal and do not depend on the size of the portion.

When used once in a serving of more than 2 g, Leponex often causes death as a result of the development of an aspiration type of pneumonia or cardiac arrest. But there is also information about the recovery of people who used drugs in portions of more than 10 g.

In addition, there is information about the development of a life-threatening coma (sometimes fatal) in people who took 0.4 g of the substance 1-fold (an increased risk of such an intense effect of the drug on the body is observed in adults who use it for the first time).

The introduction of 0.05-0.2 g of the drug in pediatrics leads to the development of a strong sedative effect with the development of coma (but death did not occur).

In case of drug overdose, the following manifestations are noted: lethargy, disorder of consciousness, severe drowsiness, appearance of visions, coma, disappearance of reflexes, increased emotional arousal, and extrapyramidal disorders. In addition, there is delirium, tachycardia, hyperreflexia, mydriasis, visual diseases, hypersalivation, convulsions, collapse, cardiac rhythm disorder, temperature changes, a decrease in blood pressure values, breathing problems (up to its stop), and aspiration pneumonia.

In the case of the development of such signs, you must adhere to the following instructions:

• if less than 6 hours have passed since the moment of drug intake, it is required to undergo gastric lavage and give the patient adsorbing agents;
• peritoneal or hemodialysis should not be carried out, because there is no information about the effectiveness of such procedures in case of Lepononex poisoning;
• perform appropriate symptomatic procedures, at the same time constantly monitoring the work of the respiratory system and the cardiovascular system, as well as the values of acid-base balance (in the case of low blood pressure, adrenaline is prohibited);
• monitor the patient’s clinical condition for at least 5 days, because there is a probability of delayed development of intoxication manifestations.

[18], [19], [20], [21], [22],

Interactions with other drugs

Drug interaction.

The introduction together with medicines that lead to severe bone marrow dysfunction can cause additive toxicity in relation to the work of the bone marrow, which is why these drugs cannot be combined.

The drug enhances the therapeutic effect of MAOI, benzodiazepines, ethyl alcohol with antihistamines, as well as systemic anesthetics.

Introduction in combination with psychotropic substances (or the use of Leponex after the use of psychotropic drugs) is prohibited or done with extreme caution, because with such a combination a collapse may occur with the likelihood of pronounced (or complete) suppression of cardiac and respiratory activity.

Introduction together with antihypertensive and anticholinergic drugs, as well as agents that slow down the activity of the respiratory system, causes mutual potentiation of therapeutic effects.

When combined with lithium substances and drugs that affect the work of the central nervous system, potentiation of the risk of the occurrence of CSN is noted.

The drug weakens the hypotensive effects of α-adrenergic and norepinephrine.

Combination with adrenaline leads to the blocking of the vasoconstrictor effect of this substance.

Use with valproic acid can cause intense epileptic seizures (even in individuals without this diagnosis), and in addition, acute mental impairment, which is marked by strong changes in consciousness and vision (delirium).

Interaction pharmacokinetic characteristics.

Substances that induce or slow down the action of the hemoprotein P450 isoenzymes can lead to a change in the activity of drug metabolism.

Funds that induce the activity of the hemoprotein P450 enzymes can reduce the plasma values of the drug.

The elements that slow down the action of the hemoprotein P450 enzymes lead to a hyperconcentration of the drug inside the blood.

In the case of a sharp decrease in the nicotine indices inside the patient's body (for example, due to a sudden cessation of smoking), serum hyperconcentration of the drug develops, which leads to an increase in its negative effect on the organism.

When used with erythromycin, cimetidine or fluvoxamine, a change in the drug's metabolic processes is noted.

Use together with substances that slow down the activity of the protease, as well as with fungicidal agents can increase the plasma values of drugs, thereby increasing its toxicity.

Paroxetine, fluoxetine, and caffeine with sertraline substantially increase Leponex blood counts.

[23], [24], [25], [26], [27]

Storage conditions

Leponex is required to be kept in a dry and dark place, with temperature indicators not exceeding 30 ° C.

[28]

Shelf life

Leponex is allowed to use for a 3-year term from the date of sale of the pharmaceutical product.

Application for children

Appropriate testing regarding the medical effect and safety in pediatrics has not been performed.

[29], [30], [31], [32]

Analogs

Analogues of drugs are drugs Adagio, Nantarid, Zolafren and Azaleptin with Olan, and in addition Azaleptol, Parnasan with Azapine, Clozapine and Seroquel with Hedonin. Also on the list are Zyprexa, Olanzapine, Queteron with Egolanza, and Ketilept with Skizoril.

[33], [34], [35], [36], [37], [38],